Hearing loss is the most common sensory impairment, affecting 1 to 6 per 1000 newborns, nearly 10% of the adult population and 50% of those over age 75. Presbycusis is the most common cause of hearing loss, involves age-related degeneration of the inner ear, and results in a sensorineural hearing loss beginning at the high frequencies and progressing to the middle and low frequencies. Although animal models and human studies support a link between hypercholesterolemia and sensorineural hearing loss that implicates pathologies affecting the cochlea, auditory nerve and/or central auditory pathways, fundamental information is lacking to explain this relationship. Mechanistic evidence and knowledge of the relative quantities, biochemical states and species of lipids in the cochlea and how cell functions are affected by altered cholesterol homeostasis are also absent. We hypothesize that cholesterol homeostasis is essential for hearing function and maintenance, and that changes in cholesterol lead to decreased cochlear and hearing function. I propose to determine how acute and chronic elevation of systemic cholesterol affect cochlear cholesterol homeostasis and hearing function and to elucidate the underlying pathologies and mechanisms by which severe hypercholesterolemia affects the adult and aging cochlea. These studies will define the extent and temporal nature of the relationships between alterations in serum cholesterol, cholesterol homeostasis in the cochlea and auditory function, as well as develop an understanding of the pathology underlying this relationship. Hearing loss is becoming an increasing challenge to public health as lifespan increases and the general population ages. As such, the rising prevalence of obesity and hypercholesterolemia demands a better understanding how cholesterol homeostasis influences cochlear cellular activities and hearing function. The outcomes from this proposal will form a crucial basis to develop new therapeutic approaches to preserve auditory function and/or treat age-related hearing loss. PUBLIC HEALTH RELEVANCE: Hearing loss has become an increasing challenge to public health as lifespan increases and the general population ages. As such, the rising prevalence of obesity and hypercholesterolemia demands a better understanding of how cholesterol homeostasis influences cochlear cellular activities and hearing function. The outcomes from this proposal will form a crucial basis to develop new therapeutic approaches to preserve auditory function and/or treat age-related hearing loss.